Breast-feeding accounts for a substantial proportion of mother-to-child HIV transmission in areas of the world where safe alternatives for infant feeding are not available. Understanding the mechanisms involved in oral transmission of HIV via breast milk and determining the correlates of transmission can lead us to develop specific therapeutic agents that will significantly lower or eliminate the risk of HIV transmission by this route. To decipher the virological and immunological variables involved in HIV transmission via breast milk, we will utilize the SIV-infected rhesus macaque model for mother-to- infant transmission and a well characterized virus inoculum, SIV/ DeltaB670. In this study we will: 1.) Determine the relationship between virus levels in breast milk and oral infection of the infant by inoculating lactating macaque females with SIV after parturition. We will quantitate virus loads in breast milk by QC-PCR at biweekly intervals to determine the correlation between virus levels and infant infection. Viral genotypes expressed in milk will be identified by dideoxy sequencing of the envelope gene and compared to those expressed in maternal plasma and infected infants to determine if only selected variants are transmitted to infants. 2.) Determine if immune responses in a chronically-infected macaque mother provide protection against oral transmission of virus in some infants. We will evaluate the levels of SIV-specific immunoglobulin in breast milk of chronically-infected macaque mothers and measure the levels of maternally-acquired SIV- specific IgG in infant plasma and saliva. We will also evaluate the presence of SIV-specific cellular immune responses in the infant that may have developed through in utero or low-dose breast milk exposure to SIV. 3.) Determine if the immune responses present in an infant born to a chronically-infected mother can protect them from oral challenge with SIV. The levels of SIV-specific maternally-acquired IgG in plasma and saliva will be quantitated and CTL responses will be measured in the infants prior to challenge. 4.) Evaluate the effectiveness of a therapeutic agent, (R)-9-(2-phosphonylmethoxypropyl) adenine (PMPA) on preventing transmission of virus to breast-fed infants. We will measure virus loads in breast milk and plasma of treated macaques and compare these levels to those found in the untreated controls. These studies will also determine how PMPA treatment affects the humoral and cellular immune responses in the lactating female and the infant that help to prevent transmission.